Lead Investigator Highlights ECHELON-1 Lymphoma Data From North American Subgroup

Radhakrishnan Ramchandren, MD

The North American subgroup analysis of the phase III ECHELON-1 trial revealed more than double the improvement seen with brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (A+AVD) compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus the primary study findings in patients with advanced Hodgkin lymphoma, explained lead author Radhakrishnan Ramchandren, MD.

The initial results of the global study indicated a 5.1% benefit with A+AVD in 2-year modified progression-free survival (mPFS) compared with ABVD. However, in an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Ramchandren noted that benefit was not distributed globally. The subgroup analysis revealed an absolute difference of 10.6% in mPFS per independent review facility and an 11.7% difference in PFS per investigator review at 2 years.¹

“It is unlikely to be a statistical anomaly,” said Ramchandren. “That being said, it is a subgroup analysis and must be evaluated prospectively to be confirmed. The difference is more than double what we saw globally and may suggest a benefit for A+AVD that is larger in the North American component as opposed to other parts of the world.”

In March 2018, the FDA approved the frontline combination of brentuximab vedotin and chemotherapy for adult patients with stage III/IV classical Hodgkin lymphoma based on the ECHELON-1 results.²

OncLive: Can you provide an overview of your lectures on Hodgkin lymphoma and T-cell lymphoma?

In the interview, Ramchandren, associate professor, Wayne State University School of Medicine, Karmanos Cancer Institute, gave an overview of the treatment landscape in Hodgkin and T-cell lymphoma before delving into the results of the North American subgroup analysis of the ECHELON-1 trial.Ramchandren: Hodgkin lymphoma is a disease that occurs in young individuals. It has been a landmark condition because we have historically had early success in treating it. However, this has come at the cost of toxicities—both acute and long-term—for patients who survive. There are patients who unfortunately don't respond to standard chemotherapy and radiation and relapse. For those patients, autologous stem cell transplant (ASCT) is an option. However, some of those patients can't achieve a remission and go to transplant or are unable to go to transplant for other reasons. For those individuals, expectations are very short in terms of lifespan and quality of life.

New drugs have been developed over the course of the last decade in Hodgkin lymphoma, which have been groundbreaking in terms of their mechanism of action and activity. They have been evaluated in earlier lines of therapy and in combination with chemotherapy. Most recently, the ECHELON-1 data incorporated A+AVD versus standard therapy with ABVD in advanced-stage disease.

A+AVD showed a benefit in mPFS. This is one of the first, if any, studies that incorporated a novel agent to a chemotherapy backbone in Hodgkin lymphoma and showed this benefit.

Secondarily, checkpoint inhibitors have shown significant activity in the relapsed setting. Now, multiple studies are also evaluating this in the frontline setting, so it's a very exciting time.

T-cell lymphoma is a relative rarity in the lymphoma world in comparison to B-cell lymphomas. Only about 10% to 15% of people who have lymphoma have T-cell lymphoma. They're largely broken down into 3 categories: cutaneous, systemic, and leukemic. Unfortunately, the outcomes for these patients are poorer than those with B-cell lymphoma.

Why has immunotherapy shown more success in Hodgkin lymphoma as opposed to other hematologic malignancies?

Improvements in therapy have been somewhat sluggish. That being said, in the past decade, there have been great advances in understanding the biology of this disease. The incorporation of novel agents has become more common, particularly in the relapsed setting. There have been studies looking at incorporating these agents in the frontline setting as well. We are eagerly awaiting some of these results. In the past year, there have been approvals for novel drugs in the T-cell lymphoma world. If we understood the biology not only of Hodgkin lymphoma, but other tumors better, I would have a better answer for you. I will say there is something to be said for exceptions to the rule. Hodgkin lymphoma certainly seems to be an exception in its response rate. There is much we can learn about immune evasion and malignancy through Hodgkin lymphoma. This disease is unique in the particular microenvironment it espouses, and its ability for a malignant cell to coordinate its microenvironment and evolve over time.

My instinct is not all immune evasion is the same. Obviously, there is a proportion of patients with solid tumors and other lymphoid malignancies who benefit from checkpoint therapy, but this is largely the minority. However, chimeric antigen receptor (CAR) T cell-therapy, which evaluates an immunotherapy that incorporates a different methodology, seems to be much more active in diffuse large B-cell lymphoma or acute lymphoblastic leukemia.

Could you speak to the North American subgroup analysis of the ECHELON-1 trial?

It so happens that in Hodgkin lymphoma, the PD-1 axis is very important. It may give us a better understanding of the biology of this particular form of immune evasion that can be applied more generally to other tumors. The North American subgroup analysis of the ECHELON-1 study was evaluated largely because of potential regional differences in the outcomes in the primary study presented at the 2017 ASH Annual Meeting. In the global study, there was a 5% benefit for patients who received the experimental arm in mPFS. The aspect that was interesting is that benefit was not equally distributed globally.

When we looked specifically in North America, there was a larger proportion of patients who benefitted—–10% to 12%––as opposed to 5% with the experimental arm. There was an improvement both in the success of the experimental arm compared with the international results and outcome of the control arm. It's unclear why that benefit exists, but certainly the number of patients on the North American subgroup analysis was substantial; they accounted for approximately 40% of 1300 patients on study.

Is there anything else from the subgroup analysis that you would like to emphasize?

There may be several reasons for this. There may be biologic differences in the disease and regional differences in drug metabolism. There may also be differences in practice patterns between countries that may help us better define what the best way to use A+AVD moving forward is. It's clear that there is activity in the experimental arm in mPFS, which was the original study endpoint. This advantage persisted even when we looked at traditional PFS. This was the first demonstration of traditional PFS maintaining that advantage. Since modified PFS was a novel endpoint, there were questions about whether that translates to traditional PFS. It did seem that the translation occurred. In fact, it suggests that A+AVD appears to be superior to ABVD in North America.

Secondly, the characteristics of the North American patients from a risk profile were very similar to those in the global population. There were no distinct differences that we could identify either between the 2 arms or from the North American population to the global population. This suggests that is not a “red herring” in the evaluation.

Are there any additional analyses that you would like to do based on these findings?

Thirdly, the toxicity profile was also similar. The same issues that apply with the global population—that is to say neuropathy and febrile neutropenia—exist in the American population. Growth factor support should be given when A+AVD is used in contrast to ABVD. That evaluation of peripheral neuropathy is an important component for physicians to consider when using either ABVD or A+AVD.One of the questions that has been raised is the best way to dose delay or dose reduce these drugs. When you discuss 4 different drugs in 1 therapeutic regimen, there are variations in practice habits. A clear picture of the best way to do that is being evaluated in the North American cohort subgroup analysis. I'm looking forward to seeing [those data].

Also, the growth factor support that was used as primary prophylaxis was used in a minority of patients. A prospective study confirming that growth factor support is needed and maintains a level of benefit in terms of febrile neutropenia that we saw in the global study. That trial is beginning as well.

Ultimately, as a researcher and a clinician, we have 2 amazing drugs that have shown a great deal of activity in Hodgkin lymphoma. We have a platform that looks at risk-adapted strategies. Figuring out the best way to incorporate both novel agents in a risk-adaptive way would be ideal so we can minimize toxicity for patients who may not need the full-blown novel regimens plus chemotherapy and/or radiation—and also identify patients who need these novel agents in conjunction with chemotherapy.

As an investigator and a physician who practices in North America, it's important to look at regional differences. It speaks to the population of patients we treat in North America. That's always a critical component to any study process. I'm very pleased to see that it was done and that it shows a significant benefit.

References

1. Ramchandren R, Advani R, Ansell S, et al. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. J Clin Oncol. 2018;36(suppl; abstr 7541). doi: 10.1200/JCO.2018.36.15.
2. Connors J, Jurczak W, Straus D J., et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV hodgkin lymphoma (HL): the phase 3 echelon-1 study. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 6.